Prostaglandins

ABSTRACT

Novel bicyclo [2,2,1] heptanes and hept-2Z-enes are substituted at the 5-position by a 6-carboxyhex-2-enyl group or a modification thereof, and at the 6-position by an aldoxime or ketoxime group which is O-substituted by an aliphatic hydrocarbon residue, an aromatic residue, or an aliphatic hydrocarbon residue substituted directly or through an oxygen or sulphur atom by an aromatic residue. Such compounds may be prepared by the action of an oximating agent on an intermediate which is substituted at the 6-position by an aldehydic or ketonic carbonyl group. The compounds are of value for use in pharmaceutical compositions particularly in the context of the inhibition of thromboxane activity.

This application is a divisional of copending application Ser. No.205,964, filed Sept. 3, 1980, entitled "Prostaglandins", now U.S. Pat.No. 4,368,332.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to biologically active compounds and inparticular to certain novel compounds exhibiting activity at thromboxanereceptor sites.

Thromboxane A₂ (TXA₂), which is derived from arachidonic acid viaprostaglandin H₂ (PGH₂), is implicated in several potentially noxiousactions on various body systems, including platelet aggregation,bronchoconstriction and pulmonary and systemic vasoconstriction. ThusTXA₂ may be involved in the normal sealing of blood vessels followinginjury but in addition may contribute to pathological intravascularclotting or thrombosis. Moreover, the constrictor actions of TXA₂ onbronchiolar, pulmonary vascular and systemic vascular smooth muscle maybe important in the development of several anaphylactic conditionsincluding bronchial asthma. There is also some evidence to implicatePGH₂ and TXA₂ in the genesis of inflammation.

It is an object of the present invention to provide compounds havingactivity at thromboxane receptor sites, and most especially to toprovide compounds which are inhibitors of thomboxane activity and aretherefore of interest in one or more areas of medical treatmentincluding the treatment of thrombotic disorders, the treatment ofanaphylactic disease states, and treatments utilising anti-inflammatoryagents.

SUMMARY OF THE INVENTION

The present invention comprises a compound being a bicyclo[2,2,1]heptaneor hept-2Z-ene which is substituted at the 5-position by a6-carboxyhex-2-enyl group is a modification thereof as defined herein,and at the 6-position by an aldoxime or ketoxime group which isO-substituted by an aliphatic hydrocarbon residue, an aromatic residueor an aliphatic hydrocarbon residue substituted directly or through anoxygen or sulphur atom by an aromatic residue.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Certain of the compounds containing a modified 6-carboxyhex-2-enyl groupact through the conversion of the modified group back to the unmodifiedgroup in vivo. In addition to such bioprecursors, the invention alsoextends in general to other pharmaceutically acceptable bioprecursorsfor the bicyclo[2,2,1]heptanes and hept-2Z-enes described above, such abioprecursor being a compound having a structural formula different fromthe active compound but which upon administration is converted theretoin vivo.

Modifications of the 6-carboxyhex-2-enyl group which may be made incompounds according to the present invention are of two types. Firstly,there are modifications which involve alteration of the hex-2-enyl groupby one, or where appropriate by a combination, of the following: (a)reduction of the double bond optionally accompanied by the replacementof a carbon atom at the 5, 6 or even 7 position relative to the C₁ ofthe carboxylic acid group by a sulphur or particularly an oxygen atom;(b) alteration of the position of the double bond, for example to the4,5 position; and (c) shortening or lengthening of the carbon chain,particularly by one or two methylene groups and conveniently at the endof the chain adjacent to the carboxy group.

The second form of modification, which may if desired be combined with amodification of the first type, involves conversion of the carboxy groupto a functional derivative including salts thereof. Functionalderivatives described in the prostaglandin art are of particularinterest, including esters such as alkyl esters, amides such as thosecontaining the group --CONHSO₂ CH₃ and variants thereon, and salts withvarious physiologically acceptable cations. Specific examples of saltsare those with an alkali metal such as sodium or with quaternaryammonium ions or amines such as tris. As mentioned above, it will beappreciated that many of such compounds are in fact bioprecursors forthe corresponding compound containing a carboxy group to which they areconverted in vivo.

Ketoxime groups, --C(R)═NOR', in which R' is as defined above for theO-substituent, more usually contain organic groups R of the same generaltype as described for R', for example particularly aliphatic hydrocarbonor aromatic residues, or alternatively aliphatic hydrocarbon residueswhich are substituted, especially directly, but also through an oxygenor sulphur atom by an aromatic residue, specific examples beingdescribed later in relation to R'. Aldoxime groups, --CH═NOR' arehowever of particular interest.

Aliphatic hydrocarbon residues constituting R' may conveniently be ofone to five, six, seven, eight, nine, ten or even more carbon atoms,being for example a branched or unbranched alkyl group such as methyl,ehtyl, propyl, butyl, amyl, etc. Aromatic residues constituting R' arealso of some interest and may be hydrocarbon or heterocyclic residues,which may be unsubstituted or substituted. The heterocyclic residues aremore generally linked through a carbon atom so that residues such aspyrid-2-yl, pyrid-3-yl and pyrid-4-yl are of particular interest.Aromatic hydrocarbon residues such as phenyl are, however, of greaterinterest and these, and also the heterocyclic residues, may besubstituted by one or more of various types of group, particularly bysubstituents being or containing a halogen residue (referred tohereinafter as `a halogen substituent`), for example chloro andespecially fluoro, and also halogen substituted alkyl groups such asCF₃, but also other substituents such as sulphonamide groups which mayoptionally be N-substituted, amino groups which may be free orsubstituted, for example dimethylamino, hydroxyl groups, methoxy andother higher alkoxy groups containing alkyl groups as described above,etc. Substitution may be present at one or more of the ortho, meta andpara positions of a phenyl ring or at a combination of two or more suchpositions (including two similar positions), for example at the 2 and 4positions. The position of substitution may have quite a significaneffect upon the activity of a compound, particularly in the case ofhalogen substituents. Thus, for example, in the case of a phenoxyethylO-substituted oxime, the order of interest in the positions ofsubstitution is o>m>p whilst in the case of a benzyl O-substituted oximeit is o˜p>m, in view of the tendency, particularly with halogensubstituent, for para substitution in the former case and metasubstitution in the latter tend to lead to partial agonist activity asdiscussed hereinafter.

Of particular interest, however, are groups R' which are aliphatichydrocarbon residues substituted directly or through a sulphur orparticularly an oxygen atom by an aromatic residue. The aliphaticresidues may be of a similar size to those described above but arepreferably of three atoms, particularly of two atoms and especially ofone atom, conveniently being branched or unbranched alkylene groups suchas methylene, ethylene or propylene or corresponding trivalent groups ofsimilar size. Similar aromatic hydrocarbon and heterocyclic residues aregenerally of interest for attachment to the aliphatic residues as havealready been described above, the aromatic hydrocarbon residues againgenerally being of more interest than the heterocyclic residues.Heterocyclic residues, where used, are however of most interest whenlinked to the aliphatic hydrocarbon residue through the hetero atom suchas in pyrid-1-yl. Substitution of an aliphatic hydrocarbon residue,particularly terminally, by two or even three aromatic aromatic residuesand/or substitution through a sulphur or particularly an oxygen atom isof some considerable interest. In the latter instance, however, thealiphatic hydrocarbon residue is conveniently of at least two carbonatoms in view of the relative instability of the linkages --O--CH₂ --S--and --O--CH₂ --O--.

Examples of specific groups R' in ketoxime and aldoxime substituents--C(R)═NOR' and --CH═NOR' are: ##STR1## wherein n=1, 2 or 3, m=2 or 3,p=1, 2, 3, 4, or 5, and X=Cl, F or CF₃.

It will be appreciated that the structures of the compounds describedabove provide various opportunities for the occurence of isomerismalthough the double bond of the unsaturated ring system is of the Zconfiguration. The substituents at the 5 and 6 positions of the ring maybe in the cis or trans relationship to each other, compounds of thelatter configuration being preferred. Moreover, as the ring system isfurther substituted by a divalent bridging group, then different isomerswill exist which vary in which of the 5- and 6-substituents is disposedin a similar direction to the bridging group. Isomers of particularinterest are (illustrated for the saturated ring system): ##STR2##

It will be appreciated that in this specification the formula used toillustrate the 5-exo, 6-endo and 5-endo, 6-exo isometric forms ofcompounds of this invention show one of the two enantiomers which exist,the other having a structure which is the mirror image of thatillustrated, and that unless a resolution step is incorporated into thesynthesis of a compound, that compound will be obtained in a racemicform. Where the substituent at the 5-position is a 6-carboxyhex-2-enylgroup or a group modified therefrom but still containing the doublebond, then the configuration about this bond is preferably cis (Z)rather than trans (E). In the second substituent, although syn and antiisomerism is possible about ##STR3## the isomers are often readilyinterconvertible at room temperature and exist as a mixture which showsbiologically activity that may, however, derive predominantly from oneisomer. In addition to the foregoing isomerism, the compounds of thepresent invention will generally be resolvable into enantiomeric formsand one among these may be preferred by virtue of biological activity orphysical properties.

Examples of specific compounds according to the present invention are##STR4## and its chloro and trifluoromethyl analogues, as well as thering saturated analogues of these compounds.

Compounds according to the present invention may conveniently beprepared by using as a starting material a compound containing theunsaturated ring system and having substituents on the ring system whichare suitable precursors for those in the final compound. The formationof such an unsaturated bicyclic ring system is conveniently effected bymeans of a Diels Alder reaction. Compounds containing the saturated ringsystems are conveniently produced by reduction of the ring double bond,for example by the use of hydrogen in the presence of a catalyst such aspalladium-charcoal, such reduction more usually being effected prior tomodification of the substituents. A convenient starting materialproviding suitable precursors for the final substituents is amaleinaldehydic acid pseudo ester of formula ##STR5## wherein Yrepresents a hydrocarbon residue, preferably an aliphatic residue suchas methyl or especially ethyl. Following reaction of this compound withcyclopentadiene in a Diels Alder reaction, modification of thesubstituents provided by the ester is effected, conveniently to giveinitially a 6-carboxyhex-2-enyl group or a modification thereof and aformyl group, --CHO, which may readily be modified further as desired.

An example of such a procedure is shown at the end of the specification,following the examples for the production of a bicyclo[2,2,1]hept-2Z-enesystem (the numbering of the compounds corresponding to that used inExample 1 and which has also been followed in Example 2 for the ringsaturated analogue. The following abbreviations are employed in thescheme: Ts, toluene sulphonyl; DMSO, dimethyl sulphoxide; Et, ethyl; Bu,butyl): The use of ethoxycarbonyl rather than methoxycarbonyl groups andof ethyl rather than methyl acetal groups has been found to be of valuein this procedure. In the final stages of this procedure the acetalgroup of compound (7) is converted to a formyl group to give compound(8) or compound (8') and this formyl group is reacted with a suitablereagent or reagents to introduce the appropriate substituted oximegroup, the carboxy group of the 6-carboxyhex-2-enyl group optionallybeing protected, thereby generally giving a slightly greater yield onoximation.

The introduction of the substituted oxime grouping may be effected byreaction of a suitable oximating agent either directly with the formylgroup, in the case of aldoximes, or with the carbonyl group producedthrough the action of a Grignard reagent on the formyl group (and thesubsequent oxidation of the secondary alcohol so formed, for exampleusing Jones reagent) in the case of Ketoximes. Such secondary alcohols,which are obtained in two isomeric forms owing to the presence of a newasymmetric centre therein, and also the ketones obtained therefrom, areincluded by the present invention in view of their value asintermediates in the preparation of the O-substituted ketoximes.

The oximating agent reacted with the formyl or --C(R)═O group mayconveniently take the form of a substituted hydroxylamine, NH₂ --O--R'.Such a reaction is generally effected in the presence of a base, forexample pyridine. As indicated above, it is possible either to react theoximating agent, for example p-fluorobenzyloxyamine hydrochloride, withthe compound (8) or with a corresponding compound in which the carboxygroup is protected. Such a protected compound is conveniently obtainedfrom the compound (7), for example by reaction with aqueous acid to givecompound (8). Following reaction of the oximating agent with the formylgroup, the carboxy group is deprotected, for example byde-esterification using KOH/CH₃ OH/H₂ O. A similar choice with regard tothe nature of the 5-substituent present in the reactant exists when the6-substituent is a group C(R)═O in which R is other than hydrogen.

Modification of the 6-carboxyhex-2enyl group may be effected through theinitial introduction of a modified group or by modification of thisgroup during or at the end of the synthesis, ester formationconveniently being effected, for example, at the stage indicatedhereinbefore and amides similarly being prepared by conventionalprocedure. Indeed, the procedures for effecting the variousmodifications indicated above will be apparent from the considerableliterature existing on prostaglandin chemistry. Thus, for example oneconvenient route for the preparation of compounds containing a6-carboxyhexyl group involves, in the case of thebicyclo[2,2,1]heptanes, the reduction of the compound (7) to saturateboth double bonds. In the case of the bicyclo[2,2,1]hept-2Z-enes thecorresponding 5-(6'-carboxyhexyl), 6-formyl compound may be obtained bythe Diels Alder reaction of 8-carboxy-1-formyl-oct-1-ene andcyclopentadiene. (A separation of the two trans isomers obtained beingrequired).

It will be appreciated that the methods described above are not the onlyones which may be used for the preparation of compounds according to thepresent invention and that various alternative procedures may be used aswill be apparent to those skilled in the art of prostaglandin chemistry.

It has been found that compounds according to the present inventioninhibit the aggregatory activity of15S-hydroxy-11α-9α-(epoxymethano)-prosta-5Z,13E-dienoicacid[11,9-(epoxymethano)PGH₂ ], which is a stable TXA₂ mimic, on humanplatelets in vitro. It is believed that such inhibition is the result ofthe compounds being thromboxane antagonists and the activity of thecompounds is for convenience hereinafter discussed in these terms.Preferred compounds according to the present invention exhibit a pureantagonist activity. However antagonist and agonist activities have beenfound to be linked in some compounds and in consequence certain of thecompounds have been found to show a partial agonist activity in certaintests, such as in the test based on the contractile activity of11,9-(epoxymethano) PGH₂ on the rabbit aorta strip, although they areantagonists in the platelet test. Structural features which tend toendow a compound with a more pure antagonist form of activity are (a)the absence of a halogen substituent, particularly at the para position,in the benzene ring of a phenoxyethyl O-substituted oxime; (b) theabsence of a halogen substituent at the meta position of a benzylO-substituted oxime; and (c) the presence of two benzene rings in theoxime substituent, these rings being located, for example, on a carbonatom joined directly to the oxygen atom of the oxime group. Someactivity has also been alserved in compounds according to the presentinvention on guinea pig tracheal muscle.

Preferred compounds such as5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyloxyiminomethyl)-bicyclo[2,2,1]hept-2Z-enewhich may alternatively be named as5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyl-carboxaldoxime)-bicyclo[2,2,1]hept-2Z-eneare antagonists in the platelet test, block the aggregatory action ofarchidonic acid which is converted to TXA₂ by the platelet enzyme systemand may or may not block the aggregatory action of ADP which acts vianon-TXA₂ -sensitive systems. Moreover, they are pure antagonists in therabbit sorta strip test but do not block the contractile action ofnoradrenaline which acts on α-adrenoceptors.

Compositions according to the present invention are of interest for thetreatment of thrombotic disorders and also for the treatment ofanaphylactic disease states, for example as bronchodilators for thetreatment of asthma, etc. They additionally have potential asanti-inflammatory agents. It will be appreciated that the spectrum ofactivity shown by any particular compound will vary and that certaincompounds may be of particular interest in one of these applicationswhilst other compounds are of particular interest in another of them.Modifications of a compound can have other advantages. Thus, forexample, it has been found that the ring unsaturated compounds describedherein are usually less stable than the ring saturated compoundsalthough the latter have similar activity in general. Furthermore theuse of esters and others derivatives of the 6-carboxyhex-2-enyl groupcan have advantages in relation to slow release depot preparationthrough conversion in vivo to the active compound containing a freecarboxy group, although the low water solubility of the esters must betaken account of.

It will be appreciated that compounds showing a partial enhancing actionon thromboxane activity are also of some interest in respect of thisactivity although to a much lesser extent than with inhibitory activity.This, certain compounds according to the present invention may be ofinterest for laboratory or even for pharmaceutical purposes, for examplein the control of bleeding by topical administration which avoids anysystemic take-up, by virtue of the thromboxane enhancing facet of theiractivity which is shown under certain conditions.

The compounds may be formulated for use as pharmaceuticals for bothanimal and particularly human administration by a variety of methods,but usually together with a physiologically acceptable diluent orcarrier. The compounds may, for instance, be applied as an aqueous oroily solutionor or as an emulsion for parenteral administration, thecomposition therefore preferably being sterile and pyrogen-free. Thepreparation of aqueous solutions of compounds in which the 5-substituentterminates in a free carboxy group may be aided by salt formation. Thecompounds may also be compounded for oral administration in the presenceof conventional solid carrier materials such as starch, lactose, dextrinand magnesium stearate. Alternative formulations are as aerosols,suppositories, cachets, and, for localised treatment, as suitable creamsor drops. Without commitment to a rigid definition of dosage, which isdifficult in view of the different levels of activity, methods offormulation, and methods of administration, some general guidance may begiven. In the case of systemic administration to produce a thromboxaneantagonism the normal daily dosage which is proposed lies in the rangefrom about 0.1 mg to about 10 mg per kilogram (the average weight of ahuman being about 70 kg) and particularly from about 1 mg to about 5 mgper kilogram. It will be appreciated, however that dosages outside thisrange may be considered, for example in the case of topical applicationto produce a localised thromboxane agonism, and that the daily dosagemay be divided into two or more portions.

The invention is illustrated by the following Examples.

EXAMPLES

Although the various compounds have predominantly the isomeric formindicated, some minor contamination by other isomers, particularly bythe 5-endo, 6-endo isomer, may be present. The various compounds are allobtained in racemic form. The numbering used for the sub-sections ofExample 1 is in accordance with that used in the reaction schene at theend of the specification. In Example 2 sub-sections relating to theanalogues ring saturated compounds have been similarly numbered.

EXAMPLE 15-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyloxyiminomethyl)-bicyclo[2,2,1]hept-2Z-ene

(1) Maleinaldehydic acid psuedo-ethyl ester

30 g of redistilled furan-2-aldehyde is mixed with 600 ml dry ethanoland 300 mg of methylene blue is added. Dry air is blown gently throughthe solution and the material is irradiated with a 300 W tungsten lampfor about two days until t.l.c. in a silica gel/ether system showsessentially no remaining starting material. The solution is then stirredwith vanadium pentoxide for four hours, filtered, and the solventremoved under reduced pressure. The residual oil is distilled under highvacuum to give the title compound as an oil (23.6 g, 76%), b.p. 90°-92°C./0.2 mm.

(2) Diels Alder reaction between maleinaldehydic acid pseudo-ethyl esterand cyclopentadiene

Freshly cracked cyclopentadiene (9.0 g) is mixed with 11.0 g of thepsuedo ester (1). A gentle warming is observed and the mixture isallowed to stand overnight. The N.M.R. spectrum typically shows theformation of the adduct (2) to be complete and the material is taken tothe next step without purification.

(3) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene

The Diels-Alder adduct (2) (10 g) is heated in a mixture of triethylorthoformate (10 ml), dry ethanol (100 ml), and concentrated sulphuricacid (1 ml). The mixture darkens and after 12 hours is cooled andtreated with anhydrous potassium carbonate (5 g) and ether (150 ml).Water is then slowly added with efficient mixing to neutralise the acid.The product is extracted with ether, washed with water and distilled togive the title compound as an oil (7.3 g, 63%) b.p. 115°-120° C./0.3 mm.

(4) 5-endo-Hydroxymethyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene

The ester (3) is added in ether to lithium aluminium hydride (10%excess))in ether with stirring at reflux temperature. After theaddition, the mixture is boiled for a further 1 hour. The reaction isquenched with wet ether and then 5% aqueous sodium hydroxide toprecipitate aluminium. The colourless organic phase is filtered, driedover anhydrous potassium carbonate, and the resulting alcohol (85-90%yield) used directly in the next stage.

(5) 5-endo-Cyanomethyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene

The alcohol (4) (7 g) in 15 ml dry pyridine is added slowly at 0° C. top-toluenesulphonyl chloride (7.5 g) in pyridine (45 ml). The mixture iskept overnight at 10° C. and then quenched by pouring over ice withvigorous shaking. The product is extracted with ether, washedconsecutively with water, 0.1M sodium carbonate and brine, and thendried (K₂ CO₃) and the solvent removed to give the tosylate ester of thealcohol as a colourless oil in high yield.

The tosylate ester (12 g) in dimethyl sulphoxide (15 ml) is added withstirring to potassium cyanide (3 g) in dimethyl sulphoxide (20 ml). Themixture is heated to 100° C. under nitrogen for 6 hours and is thencooled, poured into water and the product taken into ether. The solventis removed and the residue distilled to give title compound as an oil(6.6 g, 88%), b.p. 112°-124° C./1.8 mm.

(6) 6-exo-Diethoxymethyl-5-endo-formylmethyl-bicyclo[2,2,1]hept-2Z-ene

Di-isobutylaluminium hydride (25 ml of 1M solution in hexane) is addedwith stirring over a 10 minute period to the cyano compound (5) (5.0 g)in dry toluene (70 ml) at -15° C. under nitrogen. After a further 1 hourat room temperature the reaction is terminated by the addition withcaution of methanol (6 ml), followed by saturated aqueous sodiumhydrogen tartrate (95 ml). The mixture is then stirred and heated at 40°C. for two hours. The organic phase is separated and the aqueous layeris further extracted with ethyl acetate, the combined organic solutionsbeing dried and stripped of solvent to give the product as a yellow oil.Chromatography on Florisil in benzene gives the pure title compound as acolourless oil (3.2 g, 63%), ν_(max) (film): 1725 cm⁻¹.

(7)5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene

(4-Carboxy-n-butyl)-triphenylphosphonium bromide (7.0 g) is dried at 75°C. under vacuum for 90 minutes. The white solid is cooled, the vacuum isreleased to dry nitrogen and 10 ml of dimethyl sulphoxide (10 ml) isadded followed by 15 ml of a 2M solution of dimesyl sodium in dimethylsulphoxide. The temperature is maintained at 25° C. and the aldehyde (6)(1.5 g) is added to to the deep red yield solution. After stirringovernight the solvent is removed at 55°-60° C. under vacuum. The residueis dissolved in water, extracted with ether, and the aqueous phasecarefully acidified to pH 4 with 2N HCl. The mixture is extracted withether and the ethereal solution dried and concentrated to give the titlecompound as an oil (1.34 g, 66%).

(8)5-endo-(6'-Methoxycarbonylhex-2'Z-enyl)-6-exo-formyl-bicyclo[2,2,1]hept-2Z-ene

The acid acetal (7) (5 g) in ether is treated with excess etherealdiazomethane to form the methyl ester and then the ketal protectinggroup is removed by dissolving the compound in 215 ml chloroform andadding concentrated hydrochloric acid (55 ml) to form a two-phasesystem. The mixture is extracted with ether and the ethereal solutiondried and concentrated to give the title compound as an oil (3.38 g,90%).

Note: care should be taken to avoid contact of this compound withmethanol since it very readily forms the dimethyl acetal.

(9)5-endo-(6'-Methoxycarbonylhex-hex-2'Z-enyl)-6-exo-(O-p-fluoro-benzyloxyiminomethyl)-bicyclo[2,2,1]hept-2Z-ene

The aldehyde/ester (8) (100 mg) is heated with p-fluorobenzyloxyaminehydrochloride (100 mg) in dry pyridine (5 ml) for 3 hours at 60° C. Thepyridine is removed in vacuo, the residue is partitioned between waterand diethyl ether and the ether phase is evaporated to dryness. Theproduct is purified by liquid-gel partition chromatography using a400×15 mm column of Sephadex LH20 (Pharmacia) substituted with Nedox1114 olefin oxide (Ashland Chemical Co. USA) to 50% w/w and eluting withhexane/dichlorethane (90:10 v/v) at a flow rate of 12 ml/hour. Thechromatography gives the title compound as an oil.

The p-fluorobenzyloxyamine hydrochloride is prepared as follows.

N-Hydroxyphthalimide (12.0 g) in 130 ml dimethyl sulphoxide is treatedwith anhydrous finely divided potassium carbonate (6.6 g), when the darkred colour of the anion develops. The mixture is then treated dropwiseat room temperature with p-fluorobenzyl chloride (20 g) and the mixtureis stirred overnight or until the red colour is discharged. The reactionmixture is poured into water, and the resultant crystalline product isfiltered off. Recrystallisation from ethanol givesN'-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4 g,82%), m.p. 156°-157° C.

The imide (13.5 g) is boiled in 400 ml ethanol with 99% hydrazinehydrate (2.5 g) for 2 hours. The mixture is cooled, 7 ml of conc.hydrochloric acid is added and the precipitate of phthalhydrazide isremoved by filtration. The solution is concentrated to dryness and thesalt taken up in water, washed with ether and then basified. The freebase is taken into ether to give an ethereal solution which is washedwith brine and then dried (MgSO₄). Dry hydrogen chloride gas is passedinto the ethereal solution to deposit pure p-fluorobenzyloxyaminehydrochloride which is recrystallised from ethanol as white plates (7.9g, 90%), m.p. 298°-300° C.

(9')5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyloxyininomethyl)-bicyclo[2,2,1]hept-2Z-ene

Ester cleavage in compound (9) is effected by heating in aqueousmethanol with potassium hydroxide (0.1 N) for 3 hours at 40° C. Theproduct is again purified by liquid-gel chromatography but using a400×15 mm colunn of Sephadex LH20 substituted with Nedox 1114 olefinoxide to 20% w/w and eluting with dichloroethane/hexane/ethanol(100:100:5 v/v/v) containing 0.1% v/v of acetic acid at a flow rate of12 ml/hour. The chromatography gives the title compound as an oil in50-60% overall yield from compound (8); λ_(max) (CH₃ OH) 263 nm, ε_(max)625; M.S. (methyl ester): M⁺ 371.

EXAMPLE 25-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyloxyiminomethyl)-bicyclo[2,2,1]heptane

(1), (2), (3)5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene

Maleinaldehydic acid pseudo-ethyl ester is prepared as described inExample 1 (1) and reacted with cyclopentadiene in a Diels Alder reactionas described in Example 1 (2). The Diels Alder adduct is treated withethanol under acidic conditions as described in Example 1 (3) to give5-endo-ethoxy-carbonyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene.

(3A) 5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo[2,2,1]heptane

5-endo-Ethoxycarbonyl-6-exo-diethoxymethyl-bicyclo[2,2,1]hept-2Z-ene (30g) is dissolved in 200 ml of ethanol and 0.3 g of 10% palladium oncharcoal is added. The mixture is vigorously stirred in 1 atmosphere ofhydrogen gas at room temperature. 1 molar equivalent of hydrogen gas isabsorbed and the product is then isolated by removal of the catalyst byfiltration through a Celite pad, followed by evaporation of the filtrateto give a quantitative yield of the title compound as an oil, b.p.105°-110° C./1.5 mm.

(4) 5-endo-Hydroxymethyl-6-exo-diethoxymethyl-bicyclo[2,2,1]heptane

The ester (3A) (27 g) is added in ether to a 10% excess of lithiumaluminium hydride (2.1 g) in ether with stirring at reflux temperature.The mixture is boiled for 1 hour after the addition and is then quenchedby the addition of wet ether followed by 5% aqueous sodium hydroxide toprecipitate aluminium salts. The colourless organic phase is dried overmagnesium sulphate, filtered and evaporated to give the title compoundas an oil (20 g, 91%).

(5) 5-endo-Cyanomethyl-6-exo-diethoxymethyl-bicyclo[2,2,1]heptane

The alcohol (4) (20 g) in a minimum volume of dry pyridine is addedslowly to 20 g of p-toluenesulphonyl chloride in 130 ml dry pyridinewith stirring at 0° C. The mixture is kept at 5° C. overnight and thenpoured into a water/ice mixture. The resulting precipitate is filteredoff and dried to give the tosylate ester of the alcohol in 85% yield asan off-white solid, m.p. 84°-86° C. (dec).

The tosylate (14 g) in 15 ml dimethyl sulphoxide is added to 5 g of drypotassium cyanide in 20 ml dimethyl sulphoxide. The mixture is stirredunder nitrogen and the temperature slowly raised over 1 hour to 110° C.After 5 hours the reaction mixture is cooled and poured into water. Theproduct is isolated by ether extraction, and purified by distillation togive the title compound (7.8 g, 90%), b.p. 115°-126° C./1.5 mm.

(6) 6-exo-Diethoxymethyl-5-endo-formylmethyl-bicyclo[2,2,1]heptane

The cyano compound (5) (20 g) is stirred at -15° C. in 200 ml drytoluene under nitrogen. Di-isobutylaluminium hydride (113 ml of a 1Msolution in hexane) is added to the substrate over 25 minutes and themixture allowed to reach room temperature. After 1 hour, methanol (30ml) is cautiously added, followed by 400 ml of saturated aqueous sodiumhydrogen tartrate. The mixture is stirred and heated at 40° C. for 2hours. The upper organic layer is separated and the aqueous phasefurther extracted with ethyl acetate. The combined organic solutions aredried (MgSO₄) and the solvent removed to give a yellow oil. This ischromatographed on Florisil in benzene to give the pure title compoundas a colorless oil (17.2 g, 85%), ν_(max) (film): 1725 cm⁻¹.

(7)5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-diethoxymethyl-bicyclo[2,2,1]heptane

(4-Carboxy-n-butyl)-triphenylphosphonium bromide (23.3 g) is dried at75° C. under vacuum for 2.5 hours. The resulting white solid is thencooled, the vacuum released to dry nitrogen, and 30 ml of dimethylsulphoxide is added. A 2M solution of dimesyl sodium in dimethylsulphoxide (50 ml) is added slowly while the mixture is maintained at25° C. with a water bath. After 15 minutes the aldehyde (6) (5.0 g) isadded to the deep red ylide thus produced. The mixture is stirredovernight and then the solvent is removed at 55°-60° C. under vacuum.The residue is dissolved in water, and the aqueous phase is extractedwith ether and is then carefully acidified to pH4 with 2N HCl. Theprecipitate is extracted into ether and the ethereal solution is driedand concentrated to give the title compound as an oil 3.7 g, 55%).

(8') 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl-bicyclo[2,2,1]heptane

The acid acetal (7) (1.8 g) is dissolved in 200 ml chloroform and 50 mlof concentrated hydrochloric acid is added to form a two phase system.The mixture is vigorously stirred for 90 minutes and then extracted withether and the ethereal solution dried and concentrated. The residual oilis purified by silicic acid chromatography, the oil being applied to thecolumn (prepared by slurrying 10 g of Unisil silicic acid--ClarksonChemical Co. USA--in hexane and pouring into a glass chromatographycolumn) in hexane and elution being carried out with increasingproportions of diethyl ether in hexane up to pure diethyl ether. Thechromatography gives the title compound as a colourless oil (1.4 g,83%), ν(film): 795,1715 (broad), 2700 cm⁻¹ ; δ (90 mHz, CDCl₃) 1.2 to2.6 (18H,m), 5.4 (2H,m), 9.6 (1H,d).

Note: Care should be taken to avoid contact of this compound withmethanol since it very readily forms the dimethyl acetal.

(9')5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(O-p-fluorobenzyl-oxyiminomethy)-bicyclo[2,2,1]heptane

The aldehyde/acid (75 mg) is heated with 100 mg ofp-fluorobenzyloxyamine hydrochloride [prepared as described in Example 1(9)] in dry pyridine (5 ml) for 1 hr. The pyridine is removed in vacuo,and the residue partitioned between water and diethyl ether. The etherphase is evaporated to dryness and the resulting product is purified byliquid-gel partition chromatography using a 400×15 cm column of SephadexLH 20 substituted with Nedox 1114 olefin oxide to 20% w/w and elutingwith dichloroethane/hexane/ethanol (100:100:5 v/v/v) containing 0.1% v/vof acetic acid at a flow rate of 12 ml/hour. The chromatography givesthe title compound as a colourless oil (50 mg), λ_(max) (CH₃ OH) 263 nm,ε_(max) 650; M.S: M⁺ 373.

EXAMPLE 35-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[1'-(O-p-fluorobenzyoxyimino)-ethyl]-bicyclo[2,2,1]heptane

(1)5-endo-(6'-Carboxhex-2'Z-enyl)-6-exo-(1'-hydroxyethyl)bicyclo[2,2,1]heptane

5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-formyl bicyclo[2,2,1]heptane isprepared as described in Example 2 (8'). This aldehyde (250 mg, 1 mmole)is dissolved in dry tetrahydrofuran (10 ml) at 0° C. and treated undernitrogen un with stirring over 30 minutes with a 1M solution of methylmagnesium iodide in ether (2 ml). The mixture is stirred under nitrogenovernight whilst is is allowed to come to room temperature. The reactionis then quenched by the addition of dilute aqueoushydrochloric acid andthe product is extracted with ether (3×), the ether solution is driedand evaporated to give the title compound as an oil (200 mg). A smallsample is treated to form the Me ester trimethylsilyl ether and on gaschromatography mass spectroscopy on a 3% OVI column this shows a carbonvalue of 18.2, a M⁺ value of 352 and a base peak at 117. Chromatographyon a substituted Sephadex LH20 column as used in Example 2 (9') of thebulk of the oily product using a mixture of (all proportions by volume)100 parts of hexane, 100 parts of 1,2-dichloroethane, 5 parts of ethanoland 0.1% of the total of glacial acetic acid, as eluant yields theisomeric secondary alcohols differing in the configuration at the newlyintroduced asymmetric carbon atom (--CHOH.CH₃).Nmr spectroscopy on theseisomeric products in CDCl₃ gives the following δ values:

First isomer eluted: 7.3 (s. broad, 1H, OH); 5.45(m., 2H, olefinic H)3.6 (m-qxd; 1H, --CHOH), 2.5-1.0; (m, 21H, olefinic H); 1.2 (d, CH₃discernible).

Second isomer eluted: 7.8 (s. broad, 1H,OH); 5.4(m.,2H, olefinic H);3.55(m-qxd, 1H, CHOH); 2.5-1.0 (m., 18H, aliphatic H); 1.2(d, CH₃discernible).

(2) 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-acetyl-bicyclo[2,2,1]heptane

The procedure described under (1) is repeated with 600 mg of thealdehyde to give a mixture of the two isomeric alcohols (500 mg). Thismixture is dissolved in pure acetone (15 ml) and the solution is cooledto 0° C. Jones reagent (600 μl of a solution prepared by dissolving 26.7g of chromic anlydride in 23 ml of concentrated sulphuric acid anddiluting to 100 ml with water, followed by filtration) is added slowlyto the cooled solution with vigorous stirring over 15 minutes. After afurther 10 minutes stirring at 0° C. the mixture is poured into waterand the product extracted with ether. The ether solution is dried andevaporated to give the title compound as an oil (˜75% overall yield fromthe formyl compound) The methyl ester derivative on gas chromatographymass spectroscopy on a 3% OVI column exhibits a carbon value of 17.15, aM⁺ value of 278 and a base peak of 43/137 NMR spectroscopy in CDCl₃gives the following δ values. 10.0(s-broad, 1H,CooH; 5.4 (m,2H,olefinicH); 2.8-1.1(m,21H,aliphatic H); 2.2(s,CH₃ --CO,discernible).

(3)5-endo(6'-Carboxyhex-2'Z-enyl)-6-exo-[1'-(O-p-fluorobenzyl-1'-oxyimino)-ethyl)-bicyclo[2,2,1]heptane

The ketone (100 mg) prepared as described in (2) is heated withp-fluorobenzyloxyamine hydrochloride (100 mg) in dry pyridine (5 ml) at60° C. for 2 hours. The pyridine is removed in vacuo and the residue ispartitioned between water (pH 4) and diethyl ether. The ether is removedin vacuo to give an oil which is purified by liquid-gel partitionchromatography on a column of Sephadex LH 20 substituted with Nedox 1114olefin oxide to 20% w/w, eluting with dichloroethane/hexane/ethanol(100:100:5 v/v/v) containing 0.1% v/v of acetic acid. The chromatographygives the title compound as an almost colourless oil (90 mg),λ_(max)(CH₃ OH)263 nm,ε_(max) 620; M.S. (methyl ester): M⁺ 401; δ(CDCl₃) 1.85(s, about 3H, methyl H), 5.00 (s, 2H, benzyl H), 5.30 (m, 2H, olefinicH), 6.9-7.5 (m, 4H, aromatic H).

EXAMPLE 4 5-endo-(6'-Carboxyhex-2'Z-enyl)-bicyclo[2,2,1]hept-2Z-enes andheptanes containing other 6-exo substituents

The compounds of formula ##STR6## listed in Table 1 below are preparedas described in Example 1 (for ring unsaturated compounds) or asdescribed in Example 2 (for ring saturated compounds) using theappropriate oximating agent. This agent may however either be reactedwith a precursor in which the carboxy group is protected as in Example 1or it is in the free state as in Example 2. For the purposes ofcomparison, data on the compounds of Examples 1 and 2 has also beenincluded in this table. The UV data relates to the main peak or peaks ofthe spectrum of the free acid in methanolic and the MS data, unlessotherwise indicated, relates to the value obtained for the methyl esterby gas chromatography mass spectroscopy. (The methyl esters are preparedby dissolving the free acid in methanol, using warming and the additionof an excess of ethereal diazomethane to the Methanolic solution,standing, and the removal of the solvent).

The compounds of the present application are related to those of thecopending application Ser. No. 419,206 continuation of the now abandonedApplication Ser. No. 219,307 filed on Sept. 3, 1980 in our names inwhich the group=NOR' is replaced by a group=N.NHCO(NH)_(a) R' in which amay be 0 or 1. Further exemplification of groups R' is to be found inthat application.

The compounds disclosed in copending U.S. application Ser. No. 419,206filed Sept. 17, 1982 continuation of the now abandoned application Ser.No. 219,307 filed on Sept. 3, 1980 are described therein as also beinguseful for the treatment of thrombotic disorders, anaphylactic diseasestates, anti-inflammatory agents, and in general as thromboxaneantagonists. Further, the compounds disclosed in copending U.S.application Ser. No. 419,206 continuation of the now abandonedapplication Ser. No. 219,307 are also prepared from intermediates whichare bicyclo[2,2,1]heptanes or hep-2Z-enes which are substituted by aformyl group at 6-position, or with a carbonyl group produced throughthe action of a Grignard reagent on the formyl group (and the subsequentoxidation of the alcohol so formed, for example using Jones reagent) inthe case of compounds where R is aliphatic, or araliphatic. These formyl(or carbonyl) intermediates are the same as those used for thepreparation of the compounds described in the present application andclaimed in copending application Ser. No. 431,554 divisional ofcopending application Ser. No. 205,964, filed Sept. 3, 1980, entitled"Prostaglandins", now U.S. Pat. No. 4,368,332 of which the presentapplication is also a divisional. The carbonyl bicyclo[2,2,1]hept-2Z-eneintermediates are claimed herein, whilst the corresponding heptaneintermediates are claimed in said U.S. Pat. No. 4,368,332.

                  TABLE 1                                                         ______________________________________                                                        U.V. DATA M.S. DATA                                           COMPOUND          λ.sub.max                                                                          (Methyl                                         XY   R'               nm     ε.sub.max                                                                    ester) M.sup.+                            ______________________________________                                              ##STR7##        257    370    367                                       =                                                                                   ##STR8##        263    625    385                                       =                                                                                   ##STR9##        267    270    401/3                                     =                                                                                   ##STR10##       258    450    (1)                                       =                                                                                   ##STR11##       261    270    295                                       =                                                                                   ##STR12##       271    1450   397                                       =                                                                                   ##STR13##       281    1550   431/433                                   =                                                                                   ##STR14##       279    1320   415                                       H,H                                                                                 ##STR15##       263    650    387                                       H,H                                                                                 ##STR16##       267    350    403/405                                   H,H                                                                                 ##STR17##       272    380    437/439/441                               H,H                                                                                 ##STR18##       263    605    437                                       H,H                                                                                 ##STR19##       258    405    (1)                                       H,H  (CH.sub.2).sub.4 CH.sub.3                                                                      No     Chromo-                                                                              349                                                             U.V.   phore                                            H,H                                                                                 ##STR20##       234 272                                                                              10400 1790                                                                           341 (2)                                   ______________________________________                                         (1) M.sup.+ not apparent: ion at 167 (C.sub.6 H.sub.5).sub.2                  (2) Free acid by direct inlet.                                           

N.m.r. data on the bicyclo[2,2,1]heptane compounds (XY is H,H) of Table1 is presented in Table 2 below. All of the δ values relate to CDCl₃solution and are referred to (CH₃)₄ Si.

                  TABLE 2                                                         ______________________________________                                                  Ethylenic                                                                     protons of                                                                    substituent                                                                           Proton of                                                                              R' Protons                                         COMPOUND    at 5-posi-                                                                              aldoxime aliphatic                                      R'          tion of ring                                                                            group (1)                                                                              (2)    aromatic                                ______________________________________                                         ##STR21##  5.30 (m) 2H                                                                             6.6  (d) 6.20 (s) 1H                                                                          7.35 (m) 10H                            (CH.sub.2).sub.4 CH.sub.3                                                                 5.35 (m) 2H                                                                             6.5  (d) 4.00/4.05                                                                            --                                                                     (t) 2H                                          ##STR22##  5.35 (m) 2H                                                                             6.5  (d) 5.00/5.05 (s) 2H                                                                     6.9-7.4 (m) 4H                           ##STR23##  5.30 (m) 2H                                                                             6.55 (d) 5.00/5.05 (s) 2H                                                                     7.1-7.4 (m) 4H                           ##STR24##  5.30 (m) 2H                                                                             6.55 (d) 5.10/5.15 (s) 2H                                                                     7.1- 7.5 (m) 3H                          ##STR25##  5.35 (m) 2H                                                                             6.80 (d) 5.10/5.15 (s) 2H                                                                     7.4-7.7 (m) 3H                           ##STR26##  5.40 (m) 2H                                                                             7.65 (d) --     6.9-7.5 (m) 5H                          ______________________________________                                         (1) Only the signal corresponding to the proton of one of the isomers (sy     and anti) is observed as the signal corresponding to the proton of the        other isomer is obscured by the signal corresponding to the aromatic R'       protons, the strength of the signal is therefore less than 1H.                (2) The signals corresponding to these protons in the two isomers overlap     and cannot be separately recorded.                                       

EXAMPLE 55-endo-(6'-Carboxyhexyl)-6-exo-(O-p-fluorobenzyloxyiminomethyl)-bicyclo[2,2,1]heptane

(1) 5-endo-(6'-Carboxyhexyl)-6-exo-formyl-bicyclo[2,2,1]heptane

5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-diethoxymethyl-bicyclo[2,2,1]heptaneis prepared as described in Example 2 (7). This acid/acetal (300 mg) isstirred with 10% palladium charcoal (50 mg) in absolute ethanol (10 ml)for 30 minutes whilst continuously passing hydrogen gas through thesuspension. The catalyst is removed by filtration through a Whatman No.550 filter disc and the ethanol is then removed in vacuo. The oilyresidue of5-endo-(6'-carboxyhexyl)-6-exo-diethoxymethyl-bicyclo[2,2,1]heptane isdissolved in CHCl₃ (50 ml), 2N aqueous hydrochloric acid (50 ml) isadded, and the two phase system is stirred for 6 hours at roomtemperature. Water (100 ml) is then added, followed by diethyl ether(150 ml) and after vigorous shaking the organic phase is separated. Theaqueous phase is extracted with a further 150 ml of diethyl ether andthe two ether extracts are combined. Evaporation of the diethyl etherfrom the dried solution gives5-endo-(6'-carboxyhexyl)-6-exo-formyl-bicyclo[2,2,1]heptane as an oil(152 mg), ν_(max) (film) 1715 cm⁻¹ (broad); M.S. (methyl ester): M⁺ /M⁺+1 266/267-single peak;

δ(CDCl₃) 1.1-2.6 (22H, aliphatic H), 9.6 (d, 1H, CHO), 10.0 (broad,COOH).

(2)5-endo(6'-Carboxyhexyl)-6-exo-(O-p-fluorobenzyloxyiminomethyl)-bicyclo[2,2,1]heptane

The aldehyde/acid (1) (50 mg) is reacted in dry pyridine withp-fluorobenzyloxyamine hydrochloride according to the proceduredescribed in Example 2 (9') and the reaction mixture is worked upaccording to the procedure described therein to give the title compoundas an oil (49 mg, 66%, after chromatography), λ_(max) (CH₃ OH) 263 nm,ε_(max) 720; M.S. (methyl ester): M⁺ 389.

EXAMPLE 65-endo-(6'-Carboxyhexyl)-6-exo-(O-diphenylmethyl-oxyiminomethyl)-bicyclo[2,2,1]heptane

5-endo-(6'-Carboxyhexyl)-6-exo-formyl-bicyclo[2,2,1]heptane (50 mg),prepared as described in Example 5 (1), is reacted in dry pyridine withdiphenylmethyloxyamine hydrochloride according to the proceduredescribed in Example 2 (9') and the reaction mixture is worked upaccording to the procedure described therein to give the title compoundas an oil (50 mg, 58% after chromatography), λ_(max) (CH₃ OH) 248 nm,ε_(max) 415, M.S. (methyl ester): M⁺ not apparent, the spectrum beingdominated by the m/e 167 ion; δ(CDCl₃) 6.15 (s, 1H, CH (C₆ H₅)₂), 6.55(d, about 0.5H, ##STR27## other isomer not detectable), 7.30 (m, 10H,aromatic H).

EXAMPLE 7 Tests of Biological Activity

Various of the compounds described in Examples 1 to 6 are tested forbiological activity in the human platelet and rabbit aorta systems.

Human Platelet System

Platelet-rich plasma is obtained from fresh, citrated human blood.Addition of the 11,9-epoxymethano analogue of PGH₂ (1×10⁻⁷ M to 5×1-⁻⁷)causes immediate aggregation recorded as an increase in lighttransmission (600 nm). In a second experiment the individual compoundsare added 5 minutes previously to addition of the PGH₂ analogue. Thedose of the PGH₂ analogue added is then increased to a level which givesa similar response to that obtained in the absence of antagonist. Theaffinity constant, K_(B), for the compound is calculated according tothe Gaddum-Schild Equation (based on Law of Mass Action).

    ______________________________________                                        DR-1 = [B] × K.sub.B                                                                    DR = dose ratio                                                               [B] = molar concentration of                                                  compound                                                      ______________________________________                                    

Rabbit Aorta System

Spiral strips of thoracic aorta are suspended in Kreb's-Henseleitsolution and aerated with 95% O₂ /5% CO₂ at 37° C. Tension changes arerecorded with a Grass FTO₃ force transducer. Initially, cumulative doseresponse curves to 11,9-(epoxymethano) PGH₂ (2×10⁻⁹, 1×10⁻⁸, 5×10⁻⁸ and2.5×10⁻⁷ M) are obtained. In a second experiment the individualcompounds are added 30 minutes previously to the addition of the seriesof agonist doses. Affinity constants are calculated as above.

Results typical of those obtained for the various compounds (all ofwhich are of the formula shown at the beginning of Example 4 exceptwhere otherwise indicated) are shown in Table 3. As a standard ofcomparison, the affinity constant of the potent muscarinic receptorantagonist atrophine is 1×10⁹ liters/mole.

                  TABLE 3                                                         ______________________________________                                                         AFFINITY                                                                      CONSTANTS × 10.sup.-5                                                   liters/mole                                                  COMPOUND           Human                                                      X,Y   R'               Platelets Rabbit Aorta                                 ______________________________________                                               ##STR28##       1.9       15                                           =                                                                                    ##STR29##       4.0       36                                           =                                                                                    ##STR30##       2.1       67                                           =                                                                                    ##STR31##       510.sup.(1)                                                                             5.9                                          =                                                                                    ##STR32##       0.50      25                                           =                                                                                    ##STR33##       1.0       .sup.(2)                                     =                                                                                    ##STR34##       0.4       .sup.(2)                                     H,H                                                                                  ##STR35##       5.8       23                                           H,H                                                                                  ##STR36##       --        .sup.(2)                                     H,H                                                                                  ##STR37##       5.9       .sup.(2)                                     H,H                                                                                  ##STR38##       2.8       42                                           H,H                                                                                  ##STR39##       480.sup.(1)                                                                             1.9                                          H,H   (CH.sub.2).sub.4 CH.sub.3                                                                      1.7       1.5                                          H,H.sup.(3)                                                                          ##STR40##       0.83      --                                           ______________________________________                                         .sup.(1) significant antagonism of ADP and thrombin is shown by these two     substances; K.sub.B (ADP) = 190 × 10.sup.5. The other compounds do      not block ADP, having K.sub.B (ADP) of <0.25 × 10.sup.5.                .sup.(2) Partial agonist.                                                     .sup.(3) Double bond in substituent at 5position of ring is also reduced      in this compound.                                                        

We claim:
 1. A compound which is a bicyclo[2,2,1]hept-2Z-ene substitutedat the 5-position by a group of the formula --R¹ --COQ, where R¹ isselected from the group consisting of C₄ -C₈ alkyl;--CH₂--CH═CH--(CH₂)_(m) --, where m is an integer from 1 to 5; --CH₂ --CH₂--CH═CH--(CH₂)_(n) --, where n is an integer from 0 to 4; --X--(CH₂)_(p)--, where p is an integer from 3 to 7; --CH₂ --X--(CH₂)_(q) --, where qis an integer from 2 to 6; --CH₂ --CH₂ --X--(CH₂)_(m) --; and--CH═CH--(CH₂)₃ --; wherein X is O or S; COQ is carboxy, aphysiologically acceptable carboxylate salt, a branched or unbranched C₁-C₅ alkyl ester or CONHSO₂ CH₃ ; and wherein said bicyclo[2,2,1]hepteneis substituted at the 6-position by a grouping of the formula ##STR42##in which R₄ is selected from the group consisting of unsubstituted C₁-C₁₀ branched or unbranched aliphatic hydrocarbon residues and C₁ -C₁₀branched or unbranched aliphatic hydrocarbon residues substituted by Ar,--OAr, or --SAr, where Ar is a phenyl or pyridyl residue which isunsubstituted or substituted by one or more substituents selected fromthe group consisting of halogen, halogen substituted C₁ -C₅ branched orunbranched alkyl groups, sulphonamido groups, amino groups, hydroxy andC₁ -C₁₀ alkoxy groups; R₂ represents hydrogen and R₃ represents ahydroxy group, or R₂ and R₃ together represent the oxygen atom of acarbonyl group.
 2. A compound according to claim 1, wherein R¹ isselected from the group consisting of C₅ -C₇ alkyl,--CH₂--CH═CH--(CH₂)_(m) --, where m is an integer from 2 to 4; --CH₂ --CH₂--CH═CH--(CH₂)_(n) --, where n is an integer from 1 to 3; --X--(CH₂)_(p)--, where p is an integer from 4 to 6; --CH₂ --X--(CH₂)_(q) --, where qis an integer from 3 to 5; --CH₂ --CH₂ --X--(CH₂)_(m) --; and--CH═CH--(CH₂)₃ --; where X is O or S.
 3. A compound according to claim1, wherein the substituent at the 5-position is--(Z--)CH₂ --CH═CH--CH₂--CH₂ --CH₂ --COQ.
 4. A compound according to claim 1 wherein thesubstituent at the 5-position is--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂--COQ.
 5. A compound according to claim 3 wherein COQ is carboxy or abranched or unbranched C₁ -C₅ alkyl ester.
 6. A compound according toclaim 4 where COQ is carboxy or a branched or unbranched C₁ -C₅ alkylester.
 7. A compound according to claim 1, in which the substituent atthe 6-position is a group of the formula:

    --C(R.sub.4)═O.


8. A compound according to claim 3 wherein the substituent at the6-position is a group of the formula:

    --C(R.sub.4)═O.


9. A compound according to claim 4 wherein the substituent at the6-position is a group of the formula:

    --C(R.sub.4)═O.


10. A compound according to claim 1, wherein R₄ is an unsubstituted orsubstituted C₁ -C₃ aliphatic hydrocarbon residue.
 11. A compoundaccording to claim 10 wherein R₄ is an unsubstituted C₁ -C₃ aliphatichydrocarbon residue.
 12. A compound according to claim 11 wherein R₄ ismethyl.
 13. A compound according to claim 7 wherein R₄ is methyl.
 14. Acompound according to claim 8 wherein R₄ is methyl.
 15. A compoundaccording to claim 9 wherein R₄ is methyl.
 16. A compound according toclaim 1 wherein the configuration about any double bond in the5-substituent is cis.
 17. A compound according to claim 1 wherein the 5-and 6-substituents are in trans relationship.
 18. A compound accordingto claim 1 wherein the 5-substituent is oppositely disposed to thebridging methylene group.
 19. The compound of claim 1 which is5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo(1'-hydroxyethyl)-bicyclo[2,2,1]heptene.20. The compound of claim 1 which is5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-acetyl-bicyclo[2,2,1]heptene. 21.The compound of claim 1 which is5-endo-(6'-carboxyhexyl)-6-exo-acetyl-bicyclo[2,2,1]heptene.